Presenilin-like GxGD Membrane Proteases Have Dual Roles as Proteolytic Enzymes and Ion Channels

Ivana Y Kuo,Jian Hu,Ya Ha,Barbara E Ehrlich

doi:10.1074/jbc.m114.629584

Abstract

The GxGD proteases function to cleave protein substrates within the membrane. As these proteases contain multiple transmembrane domains typical of ion channels, we examined if GxGD proteases also function as ion channels. We tested the putative dual function by examining two archeobacterial GxGD proteases (PSH and FlaK), with known three-dimensional structures. Both are in the same GxGD family as presenilin, a protein mutated in Alzheimer Disease. Here, we demonstrate that PSH and FlaK form cation channels in lipid bilayers. A mutation that affected the enzymatic activity of FlaK rendered the channel catalytically inactive and altered the ion selectivity, indicating that the ion channel and the catalytic activities are linked. We report that the GxGD proteases, PSH and FlaK, are true "chanzymes" with interdependent ion channel and protease activity conferred by a single structural domain embedded in the membrane, supporting the proposal that higher-order proteases, including presenilin, have channel function.

Highlights

The membrane proteases are enzymatic proteins that have transmembrane domains reminiscent of ion channels
We report that the GxGD proteases, presenilin homolog (PSH) and FlaK, are true “chanzymes” with interdependent ion channel and protease activity conferred by a single structural domain embedded in the membrane, supporting the proposal that higher-order proteases, including presenilin, have channel function
PSH Forms a Monovalent Cation Channel—As PSH and FlaK are proteases containing the same GxGD catalytic motif found in presinilin (Fig. 1A), we tested the idea that PSH and FlaK are ion channels

Summary

Background

The membrane proteases are enzymatic proteins that have transmembrane domains reminiscent of ion channels. We tested the putative dual function by examining two archeobacterial GxGD proteases (PSH and FlaK), with known three-dimensional structures Both are in the same GxGD family as presenilin, a protein mutated in Alzheimer Disease. We report that the GxGD proteases, PSH and FlaK, are true “chanzymes” with interdependent ion channel and protease activity conferred by a single structural domain embedded in the membrane, supporting the proposal that higher-order proteases, including presenilin, have channel function. We report that the GxGD proteases, PSH and FlaK, are the first true “chanzymes” with interdependent ion channel and protease activity conferred by a single structural domain embedded in the membrane

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION